Abstract: Relative perception in Wnt signaling Mutations in the Wnt pathway are found in numerous diseases, from cancers to osteoporosis to diabetes. This proposal integrates modeling and experiments to understand the quantitative nature of signaling information in the Wnt pathway, and how cells interpret this signaling information. We presented evidence recently that in sensing Wnt signal, cells do not simply sense the signaling state, but instead measure the signaling state relative to the basal state. We presented evidence that phenotype and gene expression respond to fold-changes in the transcriptional activator [unreadable]-catenin, rather than to the absolute levels of [unreadable]-catenin. Sensing fold-changes may be a more pervasive theme in signaling: it is also suggested in the RTK pathway. The fold-behavior brings to mind the Weber's Law from psychophysics that describes the relative nature of our sensory perception-suggesting a convergent evolution between sensory physiology and molecular signaling. The fold-behavior raises questions on disease mechanisms: if normal cells are sensing the relative level of [unreadable]-catenin, what happen in cancer mutations? To establish the concept of fold-change detection in molecular signaling, we will pursue the molecular mechanisms of how cells compute fold-changes in Wnt signaling and characterize the full circuit of fold-change detection. This promises to uncover a key regulatory circuit that controls how cells perceive information in Wnt signaling-and potentially a potent therapeutic target. Further, the fold-change behavior inspires a mathematical framework that will be implemented experimentally to probe the quantitative basis for tissue-specificity in Wnt signaling. This promises insights into why different mutations in the Wnt pathway are found in diseases in different tissues. Public Health Relevance: We are studying how a key pathway of cell-cell communication carries information to cells. Mutations in this pathway appear often in diseases, from cancers to osteoporosis to diabetes. We have evidence that this pathway processes information in a relative manner, just like our sensory systems-and this may have implications for understanding diseases.